Compositions and methods for sensitizing low responsive tumors to cancer therapy

Abstract

The present invention discloses compositions and methods for selectively delivering apoptosis inducing agents to the tumor prior to conventional therapeutic treatment protocol. Specifically, the present invention relates to an ensemble (or ‘AAAPT bioconjugate’) comprising an apoptogen (A) and a tumor targeting group (T), wherein the apoptogen is either connected directly to the targeting group or optionally attached through an intervening linker (L). The apoptogen may be a small or large molecule that activates apoptosis pathway and causes cell death. The targeting vector may be a small or large molecule that delivers the apoptogen selectively to the tumors. The linker may comprise simple alkylene chain or may contain functional groups that are capable of being cleaved by enzymatic process.

I claim: 
     
       1. A method for enhancing the efficacy of tumor chemotherapy, radiation therapy or radionuclide therapy agent through a priori activation of apoptosis pathways of tumors, ‘AAAPT’, said method comprising administration to a patient with a tumor
 (a) a bioconjugate of Formula 3, 
 
       
         
           
           
               
               
           
         
         and 
         (b) a chemotherapeutic agent, a radiation therapy agent, or a radionuclide therapy agent; 
         wherein 
         T is a somatostatin receptor binding agent or a cathepsin B binding agent; 
         L is —NH(CH 2 ) b CO—, —OC(CH 2 ) c NH—, —(CH 2 ) d NH—, —HN(CH 2 ) e —, —O(CH 2 ) f (CH 2 CH 2 O) g (CH 2 ) h O—, —HN(CH 2 ) i (CH 2 CH 2 O) j (CH 2 ) k NH— or -(AA) n -, wherein AA is a dipeptide; 
         subscripts ‘b’, ‘c’, ‘d’ and ‘e’ independently vary from 1-10; 
         subscripts ‘f’, ‘g’, ‘h’, ‘i’, ‘j and ‘k’ are independently vary from 1-100; 
         subscript ‘n’ varies from 1 to 10; 
         R1 is C 1 -C 20  straight or branched alkyl, C 3 -C 20  cycloalkyl, C 1 -C 20  straight or branched alkenyl, C 5 -C 10  alkyl, or C 5 -C 20  arylalkyl; 
         each of R2, R3 and R4 is independently hydrogen or methyl; 
         said chemotherapy agent comprises doxorubicin, Bevacizumab, epirubicin, paclitaxel, docetaxel, 5-fluorouracil, cyclophosphamide, cisplatin, carboplatin, vinorelbine, capecitabine, liposomal doxorubicin, gemcitabine, ixabepilone, albumin-bound paclitaxel, eribulin, irinotecan, etoposide, vinblastine, tamoxifen, methotrexate or pemetrexed; 
         said radiation therapy is external beam radiation; and 
         said radionuclide therapy agent comprises  123 I,  125 I,  131 I,  186/188 Re,  111 In,  177 Lu,  153 Sm,  89 Sr,  90 Y,  201 Pb,  32 P,  198 Au,  165 Dy,  80m Br,  67 Cu or  117 Sn. 
       
     
     
       2. The method of  claim 1 , wherein
 the cathepsin B binding agent is valine-citrulline; 
 L is —O(CH 2 ) f (CH 2 CH 2 O) g (CH 2 ) h O—; 
 subscript ‘g’ varies from 10 to 20; 
 subscript ‘h’ is 2; 
 R 1  is C 16  branched alkyl; and 
 each of R 2 , R 3 , or R 4  is methyl; 
 the chemotherapy agent is doxorubicin, Bevacizumab, paclitaxel, docetaxel, cyclophosphamide, cisplatin, carboplatin, gemcitabine, ixabepilone, eribulin, irinotecan, etoposide, vinblastine, or pemetrexed; and 
 the radionuclide therapy agent is  186/188 Re,  177 Lu,  153 Sm,  90 Y,  201 Pb, or  198 Au. 
 
     
     
       3. The method of  claim 1 , wherein
 the cathepsin B binding agent is valine-citrulline; 
 L is —(CH 2 ) d NH—; 
 subscript “d” is 3; 
 R 1  is C 16  branched alkyl; 
 each of R 2 , R 3 , or R 4  is methyl; 
 the chemotherapy agent is doxorubicin, Bevacizumab, paclitaxel, docetaxel, cyclophosphamide, cisplatin, carboplatin, gemcitabine, ixabepilone, eribulin, irinotecan, etoposide, vinblastine, or pemetrexed; and 
 the radionuclide therapy agent is  186/188 Re,  177 Lu,  153 Sm,  90 Y,  201 Pb, or  198 Au. 
 
     
     
       4. The method of  claim 1 , wherein
 the cathepsin B binding agent is valine-citrulline; 
 L is —OC(CH 2 ) c NH—; subscript “c” is 3; 
 R 1  is C 16  branched alkyl; 
 each of R 2 , R 3 , or R 4  is methyl; 
 the chemotherapy agent is doxorubicin, Bevacizumab, paclitaxel, docetaxel, cyclophosphamide, cisplatin, carboplatin, gemcitabine, ixabepilone, eribulin, irinotecan, etoposide, vinblastine, or pemetrexed; and 
 the radionuclide therapy agent is  186/188 Re,  177 Lu,  153 Sm,  90 Y,  201 Pb, or  198 Au. 
 
     
     
       5. The method of  claim 1 , wherein
 the cathepsin B binding agent is valine-citrulline; 
 L is —HN(CH 2 ) b CO—; subscript “b” is 3; 
 R 1  is C 16  branched alkyl; 
 each of R 2 , R 3 , or R 4  is methyl; 
 the chemotherapy agent is doxorubicin, liposomal doxorubicin, cisplatin, carboplatin, paclitaxel, albumin-bound paclitaxel, or docetaxel; and 
 the radionuclide therapy agent is  186/188 Re,  177 Lu,  153 Sm,  90 Y,  201 Pb, or  198 Au. 
 
     
     
       6. The method of  claim 1 , wherein
 the somatostatin receptor binding agent is octreotate; 
 L is -(AA) n -; 
 subscript ‘n’ is 2; 
 AA is the dipeptide valine-citrulline; 
 R 1  is C 16  branched alkyl; and 
 each of R 2 , R 3 , or R 4  is methyl; 
 the chemotherapy agent is doxorubicin, Bevacizumab, paclitaxel, docetaxel, cyclophosphamide, cisplatin, carboplatin, gemcitabine, ixabepilone, eribulin, irinotecan, etoposide, vinblastine, or pemetrexed; and 
 the radionuclide therapy agent is  186/188 Re,  177 Lu,  153 Sm,  90 Y,  201 Pb, or  198 Au.